Clinicopathological Characteristics and Disease Chronicity in Glomerular Diseases: A Decade-Long Study at Romania's Largest Kidney Biopsy Reference Center.

Glomerular diseases (GDs), significant causes of end-stage kidney disease, are better understood through epidemiological studies based on kidney biopsies (KBs), which provide important insights into their prevalence and characteristics. This study aims to analyze the clinicopathological features of GDs diagnosed from 2008 to 2017 at Romania's largest reference center. In this decade-long study, 1254 adult patients diagnosed with GDs were included. The local previously validated renal histopathological prognostic score was calculated for each KB using four histopathologic lesions: global glomerulosclerosis, tubular atrophy, interstitial fibrosis and fibrocellular/fibrous crescents. The mean patient age was 50 years, with a male predominance (57%). The primary referral reasons were nephrotic syndrome (46%), nephritic syndrome (37%), chronic kidney disease (12%), asymptomatic urinary abnormalities (4%), and acute kidney injury (1%). Immunoglobulin A nephropathy (IgAN) was the most frequently diagnosed GD (20%), aligning with frequencies reported in European registries. Diabetic glomerular nephropathy was the most common secondary GD (10%). It also presented the highest median renal histopathological prognostic score (2), indicating a poorer prognosis. Lower eGFR and higher proteinuria were independently associated with higher scores. This decade-long study highlights IgAN as the most frequent GD diagnosed by KB. Diabetic glomerular nephropathy was identified as the most common secondary GD. The renal histopathological prognostic score, notably high in diabetic glomerular nephropathy patients, was correlated with lower eGFR and higher proteinuria, underlining its clinical relevance.

Anti-phospholipase A2 receptor positive membranous nephropathy: investigating the link between electron microscopy stages and clinical outcome.

This retrospective, observational study sought to examine the relationship between Ehrenreich-Churg electron microscopy (EM) stages and long-term outcomes in anti-PLA2R membranous nephropathy (MN). Seventy-one patients with anti-PLA2R MN (median titer 185.7RU/mL) were followed for a median of 46 months, with end-stage kidney disease (ESKD) as the primary endpoint, and response to treatment as a secondary endpoint. Patients were grouped into stages I-II (41 patients) and stages III-IV (30 patients) for analytical purposes. Notably, the III-IV group demonstrated a lower eGFR, lower anti-PLA2R titer, but a higher chronicity score. Kaplan-Meier analysis showed shorter mean kidney survival time in stages III-IV compared to I-II (p 0.03). However, multivariate analysis using Cox regression indicated that Ehrenreich-Churg stages did not significantly influence kidney survival, but lower eGFR at diagnosis and higher histopathological chronicity score did. Remission was achieved by 64% of patients and no relationship between Ehrenreich-Churg stages and treatment response was found. The only identified risk factor for not achieving remission was the severity of hyposerinemia at diagnosis. In conclusion, while EM stages III-IV are associated with more chronic lesions and stages I-II with more active immunologic disease, the histological chronicity score seems to be a stronger predictor of long-term outcomes.

How useful is kidney biopsy for the management of glomerulopathies in the elderly?

BACKGROUND: The use of kidney biopsy in elderly individuals is still matter of discussion. The purpose of this study is to assess the utility of kidney biopsy for the management of glomerulopathies in an Eastern European cohort, targeting patients older than 65 years. METHODS: This retrospective study included 875 adults (147 older than 65 years), with biopsy-proven glomerulopathies, followed up for 71.1 (95% CI 68.2-73.9) months. The primary endpoint was chronic renal replacement therapy initiation. Statistical evaluation was performed with IBM SPSS software version 20, Analyse-it, and SAS Studio. The Kaplan-Meier method was used to estimate the time to death and the log-rank test was used for comparisons. The multivariate Cox proportional hazard analysis was used to evaluate the risk of death. RESULTS: Secondary glomerulopathies were more frequent in patients aged > 65 years (52.4% vs. 41.9%, p = 0.004). Membranous nephropathy and amyloidosis were the most frequent primary and secondary glomerulopathies in this age group. Kidney biopsy complications were low (< 4%) in both age groups. In 42% of the elderly, the result of biopsy guided the immunosuppressive therapy. While the all-cause mortality rate was higher (OR 4.2; 95% CI 2.7-6.7; p < 0.0001) in elderly individuals, the rate of renal replacement therapy initiation was similar (31.3 vs 26%; p = 0.1) in both age groups. In the competitive risk analysis, kidney survival was similar irrespective of age [CIF 0.4 (95% CI 0.26-0.53) vs. 0.34 (95% CI 0.28-0.39), p = 0.08]. However, after adjusting for the confounding factors, younger age was associated with an increased risk of renal replacement therapy (HR = 1.57, p = 0.01), along with secondary glomerulopathies. CONCLUSION: The diagnosis of an underlying glomerulopathy guided the therapy in almost one-half of the elderly patients who underwent a kidney biopsy, provided important prognostic information and had a low complications rate; kidney biopsy may therefore be considered a safe, reliable procedure in the management of glomerulopathies, even in patients over 65 years of age.

Immunosuppressive therapy versus supportive care in IgA nephropathy patients with stage 3 and 4 chronic kidney disease.

The use of immunosuppressive therapy for immunoglobulin A nephropathy (IgAN) patients with stage 3 or 4 chronic kidney disease (CKD) is controversial. We performed a monocentric retrospective study on 83 consecutive IgAN patients with stage 3 or 4 CKD and proteinuria ≥0.75 g/d (age 41 [33-56] years, 72% male, estimated glomerular filtration rate 36.1 [25.4-47.5] mL/min/1.73 m2) who received uncontrolled supportive care (Supp) (n = 36), corticosteroids/corticotherapy (CS) (n = 14), or CS combined with monthly pulses of cyclophosphamide (CS + CFM) (n = 33) between 2010 and 2017. Patients were followed until composite endpoint (doubling of serum creatinine, end-stage kidney disease (dialysis or kidney transplant) or death, whichever came first) or end of study (January 2020). Patients were followed for a median of 29 (95% confidence interval = 25.2-32.7) months, and 12 (15%) patients experienced the composite endpoint. Within the limitation of a retrospective study, our results suggest no benefit from immunosuppressive therapy in patients with IgAN with stage 3 and 4 CKD as compared with supportive care. There were no differences between the 3 studied groups regarding age, estimated glomerular filtration rate, proteinuria, Oxford classification score, arterial hypertension, and therapy with renin-angiotensin system inhibitors. Mean kidney survival time for the entire cohort was 81.0 (95% confidence interval = 73.1-89.0) months, without significant differences between the 3 groups. In univariate and multivariate Cox regression analysis adjusted for IgAN progression factors, immunosuppressive therapy was not associated with better kidney survival when compared with supportive therapy.

Negative anti-phospholipase A2 receptor antibody status at three months predicts remission in primary membranous nephropathy.

BACKGROUND: The value of anti-phospholipase A2 receptor antibody (anti-PLA2R ab) monitoring at 3 months after diagnosis in membranous nephropathy (MN) remains uncertain. METHODS: We retrospectively examined the outcome on 1 August 2020 of 59 adult patients (age 54 (44, 68) years, 69% male, SCr 1.0 (0.9, 1.3) mg/dL) diagnosed with MN (kidney biopsy, positive serum anti-PLA2R ab). The outcomes were: kidney survival; partial and/or complete remission. RESULTS: Most of the studied patients (97%) received immunosuppression, cyclophosphamide regimens were the most frequent (87%), followed by cyclosporine (10%). The median time to remission was 12.0 months and the cumulative remission rates were 34% at 6, 54% at 12, and 73% at 24 months. Forty (69%) patients had negative anti-PLA2R ab at 3 months, they had similar age, serum creatinine, albumin, proteinuria, and treatment with the group with positive ab at 3 months. In the Cox proportional hazard model, three months anti-PLA2R ab negativization (HR 0.4 (95%CI 0.1, 0.9)) was an independent predictor for remission, while baseline hypoalbuminemia (HR 3.0 (95%CI 1.5, 5.7)) was associated with absence of remission. Six (10%) patients died, mostly due to cardiovascular disease and infections. A total of five (9%) patients started dialysis. Mean kidney survival time was 50.3 months and there was no survival difference in relation to baseline anti-PLA2R ab titer (p .09) or 3 months negativization (p .8). CONCLUSIONS: Three months anti-PLA2R ab negativization seems to be a late predictor of remission, and lower serum albumin at diagnosis is an early marker for remission absence. Abbreviations: anti-P LA2R ab, anti-phospholipase A2 receptor antibody; eGFR, estimated glomerular filtration rate; ESKD, end stage kidney disease; MN, membranous nephropathy; NELL-1, neural epidermal growth factor-like 1 protein; RAAS: renin-angiotensin-aldosterone system; RBC: red blood cells; RRT, renal replacement therapy; T HSD7A, thrombospondin type-1 domain containing 7A.

Adult-onset minimal change disease: the significance of histological chronic changes for clinical presentation and outcome.

INTRODUCTION: Data on pathologic features with prognostic utility in adults with minimal change disease (MCD) are limited. We assessed the relationship between histologic chronic changes and clinical presentation and outcomes. METHODS: The consecutive records of 79 patients with MCD and minimum of 6 months follow-up were retrospectively reviewed. Kidney survival was the primary endpoint (doubling serum creatinine or dialysis initiation). Secondary endpoints were time to remission and relapse. Total chronicity score was the sum of glomerulosclerosis (0-3), interstitial fibrosis (0-3), tubular atrophy (0-3), and arteriolosclerosis (0/1). RESULTS: The median renal chronicity score was 1; 77% had minimal (0-1), 18% mild (2-4), and 5% moderate (5-7) chronicity. Fifty percent had a null score; they were younger, had higher eGFR, similar proteinuria, better renal survival, and lower mortality. Mean kidney survival time was 5.7 (95% CI 5.2-6.2) years; 89% reached a form of remission at a median of 8 weeks; 31% relapsed at a mean of 26 months. Chronic changes severity predicted both relapses and kidney survival, each one-point increase in score raised with 27% the risk of relapse and with 31% the risk of dialysis initiation. Acute kidney injury (AKI) was present in 42% of the patients; they had more often mesangial proliferation, interstitial inflammation, tubular atrophy, arteriosclerosis, podocyte villous hypertrophy, and higher chronicity score. CONCLUSION: Standardized grading of chronicity was a predictor of kidney survival and disease relapse and was related to AKI. Older patients with severe nephrotic syndrome and with increased chronicity score could represent a high-risk category.

Non-diabetic glomerular lesions in diabetic kidney disease: clinical predictors and outcome in an Eastern European cohort.

PURPOSE: Since patients' prognosis depends on the lesions identified by kidney biopsy (KB), we aimed to evaluate predictors of non-diabetic kidney disease (NDKD) in diabetic subjects and to assess their kidney outcome as compared to diabetic nephropathy (DN). METHODS: 180 adults diagnosed by KB with DN (n = 120) or NDKD (n = 60), over a 10 year time-span, were retrospectively included and followed for a mean of 48.1 (95% CI 43.1-53.1) months. Patients with superimposed specific lesions over DN and with steroid-induced diabetes were excluded. The primary endpoint was renal replacement therapy (RRT) initiation. Only subjects who were alive at the end of follow-up (73 with DN and 38 with NDKD) entered the kidney survival analysis. RESULTS: Membranous nephropathy (9%) was the most common NDKD. Predictors for NDKD were shorter duration of diabetes (OR 0.88; 95% CI 0.81-0.96, p = 0.004), absence of diabetic retinopathy (OR 0.08; 95% CI 0.01-0.44, p = 0.003), and nephrotic syndrome at presentation (OR 3.55; 95% CI 1.39-9.04, p = 0.008). Subjects with NDKD needed RRT later as those with DN [82 (95% CI 67-97.1) vs. 45 (95% CI 34-56.5) months, p = 0.001]. In an adjusted Cox model, biopsy diagnosed DN independently predicted RRT (OR 4.43; 95% CI 1.54-12.7, p = 0.006). Other predictors were lower eGFR, higher proteinuria, and absence of renin-angiotensin inhibitor therapy. CONCLUSION: As one-third of the investigated subjects had NDKD, and NDKD was associated with a better kidney survival, independently predicted by the type of glomerular lesion, KB appears the most reliable tool to guide therapy and to assess outcome in patients with diabetic kidney disease.

Is There a Role for IgA/C3 Ratio in IgA Nephropathy Prognosis? An Outcome Analysis on An European Population.

INTRODUCTION: Serum immunoglobulin A (IgA)/C3 ratio has been reported as a predictor of histological lesions and prognosis in asian patients with IgA nephropathy (IgAN). Since its validity in other populations is unclear, we aimed to evaluate the relationship between IgA/C3 ratio and renal outcome in Caucasian European patients with biopsy-proven IgAN. METHODS: We conducted a retrospective, observational study on 95 patients with primary IgAN patients diagnosed between 2010 to 2017 (70% male, age 41 (34 to 49) years, eGFR 39.4 (25.2 to 56.5) mL/ min, proteinuria 1.7 (0.8 to 3.0) g/g). The primary study composite end-point was doubling of serum creatinine, ESRD (dialysis or renal transplant) or death, whichever came first. RESULTS: Median follow-up was 30 (95% CI: 27.5 to 32.4) months; 11% developed ESRD, 10% experienced serum creatinine doubling, and 1% died. The endpoint was reached by 21% of the patients. They had lower eGFR, higher proteinuria and hematuria, and lower serum albumin. The distribution in Oxford classes was alike. The AUROC for IgA/C3 ratio was 0.60 (95% CI: 0.45 to 0.74) and generated an optimal cut-off of 2.91 (sensitivity 68%, specificity 55%). The mean event-free survival of the whole cohort was 5.2 (95% CI: 4.7 to 5.8) years. Patients with IgA/C3 ratio < 2.9 had a tendency to better renal survival (P > .05). In Cox proportional hazard ratio model, the independent predictors of a poorer eventfree survival were higher serum creatinine, higher proteinuria and increased IgA/C3 ratio, while renin angiotensin system inhibitors predicted better outcome. CONCLUSION: Our study reports evidence that supports IgA/C3 ratio as a reasonable predictor of IgAN prognosis in European patients.

Towards a simplified renal histopathological prognostic score in glomerular nephropathies.

AIMS: An important role of native kidney biopsy evaluation is to predict renal prognosis. We aimed to develop a simplified chronicity score based solely on pathological features that are easily recognisable and can be found in all glomerular nephropathies (GN). In this retrospective study, observational cohort study we included 625 patients with GN diagnosis after native kidney biopsy in a tertiary unit between 1 January 2010 and 31 December 2015. METHODS AND RESULTS: Presence of global glomerulosclerosis (GG), tubular atrophy (TA), interstitial fibrosis (IF) and fibrocellular/fibrous crescents (FC) in any grade was scored with one point; a final score was between 0 and 4 (i.e. 'absent' 0 score, 'moderate' 1-2 score, 'severe' 3-4 score). The primary endpoint was renal replacement therapy (RRT) initiation. Mean baseline estimated glomerular filtration rate (eGFR) was 55.9 ± 29.6 ml/min; during the follow-up (median = 27 months), 78 patients started RRT. The total mean renal survival time was 60.1 (58.0-62.1) months. GG (41%) was the most frequent lesion, followed by IF (25%), TA (18%) and FC (17%). Patients with absent (65.7; 63.6-67.8 months) chronicity had better renal survival than those with moderate (59.1; 56.1-62.2 months) or severe (42.7; 35.6-49.7 months) chronicity. The score was associated with renal survival [hazard ratio (HR) = 1.33; 1.08-1.64)] independently of the classical prognostic factors. Patients with moderate and severe chronicity had a two- and threefold increase in risk of RRT initiation. CONCLUSION: Our score was correlated with renal survival independently of the traditional risk factors, and could improve outcome prediction in patients with GN by reducing the interobserver variability.

Histologic predictors of renal outcome in diabetic nephropathy: Beyond renal pathology society classification.

The prognostic utility of histologic features in patients with diabetic nephropathy (DN) classified according to the Renal Pathology Society (RPS) classification is controversial. Therefore, we aimed to evaluate the relationship between histologic changes and renal outcome in DN patients.We examined the renal outcome at November 30, 2017 of 74 adult patients (median age of 54.6 years, 69% male, 81% diabetes mellitus (DM) type 2, estimated GFR (eGFR) 29.6 mL/min) with biopsy proven DN between 2010 and 2015. The primary endpoint was renal replacement therapy (RRT) initiation.Half of the patients progressed to end stage renal disease (ESRD) during follow-up; they had lower eGFR, increased proteinuria, hematuria and serum cholesterol. Regarding the pathologic features, they were more frequently in class III and IV, had higher interstitial fibrosis and tubular atrophy score (IFTA), increased interstitial inflammation, more frequent arteriolar hyalinosis and higher glomerular basement membrane (GBM) thickness. The mean kidney survival time was 2.7 (95%CI 2.1, 3.3) years. In univariate time-dependent analyses, higher RPS DN class, increased IFTA, the presence of arteriolar hyalinosis and arteriosclerosis were associated with RRT initiation.In the fully adjusted model, the clinical characteristics associated with poor renal survival were longer duration of DM, lower eGFR, increased proteinuria and higher hematuria and the only pathologic lesions to remain significant were the GBM thickness and the IFTA.In conclusion, in this European cohort, the severity of glomerular lesions evaluated with the RPS DN classification had limited utility in predicting RRT initiation. However, IFTA and GBM thickness were significantly associated with renal survival.

Thyroid autoimmunity in 72 children with type 1 diabetes mellitus: relationship with pancreatic autoimmunity and child growth.

The aim of this study was to assess the association between pancreatic and thyroid autoimmunity (TA) and determine impact of thyroid antibodies on statural growth. Seventy-two children with type 1 diabetes mellitus (TIDM) and no clinical evidence of thyroid disorders were evaluated: glycated haemoglobin (A1c), thyroid peroxidase antibodies (TPOAb), glutamic acid decarboxylase antibody (GADA), tyrosine phosphatase antibodies (IA2A), and thyroid-stimulating hormone (TSH). The score of standard deviation for height (SDS) was calculated. There were 72 patients, 38 (52.7%) boys and 34 (47.2%) girls, with a mean age of 10.89 +/- 4.26 years and a mean duration of T1DM of 3.41 +/- 2.56 years. TPOAb were present in 23.6% of patients; 12.5% of subjects were positive for GADA and 41.6% for IA2A. Patients with TA had more prevalent GADA and IA2A (23.5% vs. 9%, p < 0.001, and 58.8% vs. 36.3%, p < 0.001, respectively). A1c was higher in patients with TA (9.7% +/- 2.05% vs. 8.6% +/- 2.11%, p = 0.05). TA was associated with lower SDS (0.26 vs. 0.98, p = 0.043). TSH was higher in patients with TA (3.39 vs. 2.15 microU/mL, p < 0.05). Logistic regression analysis revealed that a negative SDS for height was independently associated with duration of diabetes (p = 0.049) and TSH (p = 0.027) but not with birth weight, A1c, and TPOAb. In conclusion, TA was found in 23.6% TIDM children. Patients with TA had significantly higher prevalence of GADA and IA2A and significantly higher A1c vs. patients without TA. Our data suggest significant association between TA and height in children with T1DM. SDS was independently associated with diabetes duration and TSH.